Since its inception, functional MRI (fMRI) using blood oxygenation level dependent (BOLD) contrast has seen an explosive growth in its applications in basic and clinical neurosciences, and continues to be the dominant method in neuroimaging. However, BOLD imaging also suffers from dispersed spatial localizations and temporal delays due to hemodynamic modulations from vasculature of all sizes, and remains a somewhat qualitative assessment of neuronal functions. Continued effort has been made to improve the spatial localization and the temporal resolution within the BOLD contrast. In more recent years, completely independent contrasts based on neuroelectric activities have been proposed and developed, and have shown initial promises in applications in vitro and in vivo. In this proposal, we will integrate the advances of hemodynamic and neuroelectric imaging in the recent years, and develop a direct MRI approach with a central focus on drastically improving the sensitivity of the neuroelectric signal. Specifically, three complementing aims, with a common emphasis on achieving a much greater sensitivity, but also with individual focuses on innovative imaging hardware, imaging software and driven neuronal oscillations, are proposed to achieve a direct MRI of ionic neuroelectric activity. First, we will develop a new multi-mode parallel receive coil to achieve high-sensitivity, high-resolution, diffusion contrast imaging for improved spatial correspondence with cortical neuronal activities; Second, we will develop a spiral echo volume imaging (EVI) technique to further improve the imaging sensitivity; Third, we will develop direct MRI methodology of ionic neuroelectric activities using synchronized gradient oscillation and high-frequency driven visual stimulation, and in conjunction with advances in the previous aims, to further gain the much needed signal- to-noise ratio (SNR) by time-locked temporal averaging within the neuronally activated regions. We anticipate that our integrated approach will allow the highest sensitivity possible to measure ionic neuroelectric signals, characterize their spatial and temporal dependences, and move significantly toward a direct and sensitive fMRI methodology for imaging cortical neuroelectric activities in vivo. PUBLIC HEALTH RELEVANCE: This project is based on an integrated approach to image cortical neuronal activities using hemodynamic and neuroelectric contrasts. We propose three specific aims to achieve this central objective, all with a central focus for a greatly improved sensitivity, but also with respective focuses on new imaging hardware, software and innovative neuronal activation paradigms. The advances from these three aims will enable time-locked detection of ionic neuroelectric currents with direct spatial and temporal specificity. We anticipate that our integrated approach will allow us to establish a solid technical foundation toward a sensitive, non-invasive, and more importantly, direct neuroimaging methodology.